Cgrp receptor antagonist compounds for topical treatment of skin disorders

Abstract

The use of a CGRP receptor antagonist compound of formula (I) for topical application is described for treating and/or preventing skin inflammatory pathologies with a neurogenic component. More specifically, use of a CGRP receptor antagonist compound of formula (I) is described for topical application for treating and/or preventing rosacea, especially type I rosacea, atopic dermatitis, psoriasis and/or acne.

1 . A method of treating a dermatological disorder, the method comprising topically administering an effective amount of a compound to an individual subject in need thereof, wherein the compound is a compound of formula I 
       
         
           
           
               
               
           
         
       
       wherein:
 Al is —CH2— or —N(R8)—; 
 Ea is selected from the group consisting of: 
 
       (1) —C(R5a)═, 
       (2) —N═, and 
       (3) —(N+—O—)═;
 Eb is selected from the group consisting of: 
 
       (1) —C(R)═, 
       (2) —N═, and 
       (3) —(N+—O—)═;
 Ec is selected from the group consisting of: 
 
       (1) —C(R5c)═, 
       (2) —N═, and 
       (3) —(N+—O—)═;
 R5a, R5b and R5c are each independently selected from the group consisting of: 
 
       (1) hydrogen, 
       (2) —C1-6alkyl, which is unsubstituted or substituted with 1-5 fluoro, and 
       (3) halo;
 R6 and R7 are each: 
 
       (1) methyl which is unsubstituted or substituted with 1-3 fluoro; or 
       (2) ethyl, which is unsubstituted or substituted with 1-5 fluoro; or
 R6 and R7 and the carbon atom to which they are attached join to form a ring selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydropyranyl, pyrrolidinyl, and piperidinyl, which ring is unsubstituted or substituted with 1-6 substituents each independently selected from the group consisting of: 
 
       (1) —C1-6alkyl, which is unsubstituted or substituted with 1-3 halo, 
       (2) phenyl, wherein the phenyl is optionally fused to the ring, and which phenyl is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of: halo, —ORa, and —C1-4alkyl, which is unsubstituted or substituted with 1-3 fluoro, and 
       (3) halo;
 R8 is independently selected from the group consisting of: 
 
       (1) hydrogen, 
       (2) —C(═O)Ra, 
       (3) —CO2Ra, 
       (4) —SO2Rd, and 
       (5) —C1-6alkyl, which is unsubstituted or substituted with 1-5 fluoro;
 R10 is independently selected from the group consisting of: 
 
       (1) hydrogen, and 
       (2) —C1-6alkyl, which is unsubstituted or substituted with fluoro;
 R11 is phenyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from the group consisting of R12, R13, R14, R15a and R15b, R12, R13, R14, R15a and R15b are each independently selected from the group consisting of: 
 
       (1) —C1-6alkyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from the group consisting of:
 (a) halo, 
 (b) —ORa, 
 (c) —C3-6cycloalkyl, and 
 (d) phenyl or heterocycle, wherein said heterocycle is selected from the group consisting of: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperdinyl, piperazinyl, pyrrolidinyl, thienyl, morpholinyl, thiazolyl and oxazolyl, which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from the group consisting of:
 (i) halo, 
 (ii) —C1-6alkyl, which is unsubstituted or substituted with 1-5 halo, and 
 (iii) —ORa, 
 
 (e) —CO2Ra, 
 (f) —C(═O)NRbRc, 
 (g) —S(O)vRd, 
 (h) —CN, 
 (i) —NRbRc, 
 (j) —N(Rb)C(═O)Ra, 
 (k) —N(Rb)SO2Rd, 
 (l) —CF3, 
 (m) —O—CO2Rd, 
 (n) —O—(C═O—)—NRbRc, 
 (o) —NRb—(C═O)—NRbRc, and 
 (p) —C(═O)Ra, 
 
       (2) —C1-6cycloalkyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from the group consisting of:
 (a) halo, 
 (b) —CN, 
 (c) —C1-6alkyl, which is unsubstituted or substituted with 1-5 halo, 
 (d) —ORa, and 
 (e) phenyl, which is unsubstituted or substituted with 1-5 substituents where the substituents are each independently selected from the group consisting of:
 (i) —ORa, 
 (ii) halo, 
 (iii) —CN, and 
 (iv) —C1-6alkyl, which is unsubstituted or substituted with 1-5 halo, 
 
 
       (3) phenyl or heterocycle, wherein said heterocycle is selected from the group consisting of: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperdinyl, piperazinyl, pyrrolidinyl, thienyl, morpholinyl, thiazolyl and oxazolyl, which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from the group consisting of:
 (a) halo, 
 (b) —ORa, 
 (c) —C3-6cycloalkyl, and 
 (d) phenyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from the group consisting of:
 (i) halo, 
 (ii) —C1-6alkyl, which is unsubstituted or substituted with 1-6 halo, and 
 (iii) —ORa, 
 
 (e) —CO2Ra, 
 (f) —C(═O)NRbRc, 
 (g) —S(O)vRd, 
 (h) —CN, 
 (i) —NRbRc, 
 (j) —N(Rb)C(═O)Ra, 
 (k) —N(Rb)SO2Rd, 
 (l) —O—CO2Ra, 
 (m) —O—(C═O)—NRbRc, 
 (n) —NRb—(C═O)—NRbRc, 
 (o) —C(═O)ORa, and 
 (p) —C1-6alkyl, which is unsubstituted or substituted with 1-6 halo, 
 
       (4) halo, 
       (5) oxo, 
       (6) —ORa, 
       (7) —CN, 
       (8) —CO2Ra, 
       (9) —C(═O)Ra, 
       (10) —NRbRc, 
       (11) —S(O)vRd, 
       (12) —C(═O)NRbRc, 
       (13) —O—CO2Rd, 
       (14) —N(Rb)CO2Rd, 
       (15) —O—(C═O)—NRbRc, 
       (16) —NRb—(C═O)—NRc, and 
       (17) —SO2NRbRc, (18) —N(Rb)SO2Rd, or
 R15a and R15b and the atom(s) to which they are attached join to form a ring selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thietanyl and tetrahydrothienyl, wherein the sulfur is optionally oxidized to the sulfone or sulfoxide, which ring is unsubstituted or substituted with 1-5 substituents each independently selected from the group consisting of: 
 (a) —C1-6alkyl, which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of:
 (i) halo, 
 (ii) —ORa, 
 (iii) —C3-6cycloalkyl, 
 (iv) —CO2Ra, 
 (v) —NRbRc, 
 (vi) —S(O)vRd, 
 (vii) —C(═O)NRbRc, and 
 (viii) phenyl, 
 
 (b) phenyl or heterocycle, wherein said said heterocycle is selected from the group consisting of: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, morpholinyl, thiazolyl and oxazolyl, which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from the group consisting of:
 (i) halo, 
 (ii) —C1-6alkyl, which is unsubstituted or substituted with 1-5 halo, and 
 (iii) —ORa, 
 
 (c) —ORa, 
 (d) halo, 
 (e) —CO2Ra, 
 (f) —C(═O)NRbRc, 
 (g) —S(O)vRd, 
 (h) —CN, 
 (i) —NRbRc, 
 (j) —N(Rb)C(═O)Ra, 
 (k) —N(Rb)SO2Rd, 
 (I) —O—CO2Rd, 
 (m) —O—(C═O)—NRbRc, 
 (n) —NRb—(C═O)—NRbRc, and 
 (o) —C(═O)Ra; 
 Ra is independently selected from the group consisting of: 
 
       (1) hydrogen, 
       (2) C1-6alkyl, which is unsubstituted or substituted with 1-7 substituents each independently selected from the group consisting of:
 (a) halo, 
 (b) —O—C1-6alkyl, which is unsubstituted or substituted with 1-6 halo, 
 (c) hydroxyl, 
 (d) —CN, and 
 (e) phenyl or heterocycle wherein said heterocycle is selected from the group consisting of pyridyl, pyrimidinyl, thienyl, pyridazinyl, piperidinyl, azetidinyl, furanyl, piperazinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and pyrazinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of:
 (i) halo, 
 (ii) —O—C1-6alkyl, which is unsubstituted or substituted with 1-6 halo, 
 (iii) —CN, 
 (iv) nitro, (v) hydroxyl, and 
 (vi) —C1-6alkyl, which is unsubstituted or substituted with 1-6 halo, and 
 
 
       (3) phenyl or heterocycle wherein said heterocycle is selected from the group consisting of pyridyl, pyrimidinyl, thienyl, pyridazinyl, piperidinyl, azetidinyl, furanyl, piperazinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and pyrazinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of:
 (a) halo, 
 (b) —CN, 
 (c) —O—6alkyl, which is unsubstituted or substituted with 1-6 halo, 
 (d) nitro, 
 (e) hydroxyl, and 
 (f) —C1-6alkyl, which is unsubstituted or substituted with 1-6 halo, and 
 
       (4) —C3-6cycloalkyl, which is unsubstituted or substituted with 1-6 halo; Rb and Rc are independently selected from the group consisting of:
 (1) hydrogen, 
 (2) C1-6alkyl, which is unsubstituted or substituted with 1-7 substituents each independently selected from the group consisting of:
 (a) halo, 
 (b) —ORa, 
 (c) —CN, 
 (d) —CO2Ra, and 
 (e) phenyl or heterocycle, wherein said heterocycle is selected from the group consisting of pyridyl, pyrimidinyl, thienyl, pyridazinyl, piperidinyl, azetidinyl, furanyl, piperazinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and pyrazinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of: 
 (i) halo, 
 (ii) —ORa, 
 (iii) —C1-6alkyl, which is unsubstituted or substituted with 1-6 halo, and 
 (iv) nitro, 
 
 
       (3) phenyl or heterocycle, wherein said heterocycle is selected from the group consisting of pyridyl, pyrimidinyl, thienyl, pyridazinyl, piperidinyl, azetidinyl, furanyl, piperazinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and pyrazinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of:
 (a) halo, 
 (b) —ORa, 
 (c) —C1-6alkyl, which is unsubstituted or substituted with 1-6 halo, 
 (d) —C3-6cycloalkyl, which is unsubstituted or substituted with 1-6 halo, 
 (e) —CN, and 
 (f) —CO2Ra, and 
 
       (4) —C3-6cycloalkyl, which is unsubstituted or substituted with 1-6 halo; or Rb and Rc and the nitrogen to which they are attached join to form a 4-, 5-, or 6-membered ring optionally containing an additional heteroatom selected from the group consisting of N, O, and S, wherein the sulfur is optionally oxidized to the sulfone or sulfoxide, which ring is unsubstituted or substituted with 1-4 substituents each independently selected from the group consisting of:
 (a) halo, 
 (b) —ORa, and 
 (c) —C1-6alkyl, which is unsubstituted or substituted with 1-6 halo, and 
 (d) phenyl; 
 Rd is independently selected from the group consisting of: 
 
       (1) C1-6alkyl, which is unsubstituted or substituted with 1-4 substituents each independently selected from the group consisting of:
 (a) halo, 
 (b) —ORa, 
 (c) —CO2Ra, 
 (d) —CN, and 
 (e) phenyl or heterocycle, wherein said heterocycle is selected from the group consisting of pyridyl, pyrimidinyl, thienyl, pyridazinyl, piperidinyl, azetidinyl, furanyl, piperazinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and pyrazinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of:
 (i) halo, 
 (ii) —ORa, 
 (iii) —C1-6alkyl, which is unsubstituted or substituted with 1-6 halo, and 
 (iv) nitro, 
 
 
       (2) phenyl or heterocycle, wherein said heterocycle is selected from the group consisting of pyridyl, pyrimidinyl, thienyl, pyridazinyl, piperidinyl, azetidinyl, furanyl, piperazinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl tetrahydropyranyl and pyrazinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of:
 (a) halo, 
 (b) —ORa, 
 (c) —C1-6alkyl, which is unsubstituted or substituted with 1-6 halo, 
 (d) —C3-6cycloalkyl, which is unsubstituted or substituted with 1-6 halo 
 (e) —CN, and 
 (f) —CO2Ra, and 
 
       (3) —C3-6cycloalkyl, which is unsubstituted or substituted with 1-6 halo; v is 0, 1, or 2; and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof. 
     
     
         2 . The method according to  claim 1 , wherein the dermatological disorder is a skin inflammatory pathology with a neurogenic component. 
     
     
         3 . The method according to  claim 2 , wherein the skin inflammatory pathology with a neurogenic component is selected from the group consisting of rosacea, atopic dermatitis, hand chronic eczema, psoriasis, facial erythema, pudic erythema, hives and acne. 
     
     
         4 . The method according to claim wherein the skin inflammatory pathology with a neurogenic component is selected from the group consisting of type I erythematous rosacea, atopic dermatitis, vulgaris psoriasis, and scalp psoriasis, acne, prurit senile nodularis and prurigo nodularis. 
     
     
         5 . The method according to  claim 4 , wherein the skin inflammatory pathology with a neurogenic component is type I erythematous rosacea, atopic dermatitis, psoriasis and/or acne. 
     
     
         6 . The method according to  claim 1 , wherein:
 Al is CH2 or —N(R8)—, wherein R8 is selected: hydrogen or C1-6alkyl, unsubstituted or substituted with 1-5 fluoro;   Ea is —C(R5a)═, or —N═;   Eb is —C(R5b)═, or —N═;   Ec is —C(R5c)═, or is —N═;   wherein R5a, R5b and R5c are independently hydrogen or halo;   R6 and R7 are ethyl, unsubstituted or substituted with 1-5 fluoro or methyl unsubstituted or substituted with 1-3 fluoro, or selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydropyranyl, pyrrolidinyl, and piperidinyl, which ring is unsubstituted or substituted with 1-6 substituents each independently selected from the group consisting of:   
       (1) —C1-6alkyl, unsubstituted or substituted with 1-3 halo, 
       (2) phenyl, optionally fused to the ring, unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of: halo, —ORa, and —C1-4alkyl, unsubstituted or substituted with 1-3 fluoro, wherein Ra is as defined in  claim 1 ; and 
       (3) halo,
 R10 is hydrogen, 
 R11 is phenyl which is unsubstituted or substituted with 1-5 halo. and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof. 
 
     
     
         7 . The method according to  claim 1 , wherein:
 Al is —N(R8)—, wherein R8 is hydrogen,   Ea is —C(R5a)═,   Eb is —C(R5b)═,   Ec is —C(R5c)═,   wherein R5a, R5b and R5c are hydrogen,   R6 and R7 and the carbon atom to which they are attached join to form an unsubstituted cyclopentyl,   R10 is hydrogen, and   R11 is a phenyl substituted with 1-5 fluor substituents.   
     
     
         8 . The method according to  claim 1 , wherein the compound is 2-[(8R)-8-(3,5-difluorophenyl)-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]-N-[(R2R)-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl]acetamide. 
     
     
         9 . A topical pharmaceutical composition comprising at least a compound of formula (I) as defined in  claim 1 , and a pharmaceutically acceptable vehicle suitable. 
     
     
         10 . The composition according to  claim 9  wherein the compound is at a concentration ranging from about 0.001% to about 10%, by weight, relative to the total weight of the composition. 
     
     
         11 . The composition according to  claim 9  comprising about 3% of the compound of formula (I) by weight, relative to the total weight of the composition. 
     
     
         12 . The composition according to  claim 9  comprising about 2% of the compound of formula (I) by weight, relative to the total weight of the composition. 
     
     
         13 . The method according to  claim 3 , wherein the rosacea is type I erythematous rosacea or type II papulopustular rosacea. 
     
     
         14 . The method according to  claim 3 , wherein the psoriasis is vulgaris, scalp, arthritic, pustular, or guttate psoriasis. 
     
     
         15 . The method according to  claim 3 , wherein the hives are acute, senile pruritus, or prurigo nodularis hives. 
     
     
         16 . The composition according to  claim 10 , wherein the concentration of the compound is from about 0.001% to about 5%, by weight. 
     
     
         17 . The composition according to  claim 10 , wherein the concentration of the compound is from about 0.3% to about 3%, by weight.